TOPICAL DELIVERY - The Importance of the Right Formulation in Topical Drug Development

BACKGROUND

Topical
formulations for pharmaceutical delivery are becoming increasingly popular.
Topical delivery has a number of advantages: the ability to deliver drug
substance more selectively to a specific site, avoiding fluctuations in drug
levels, inter- and intra-patient variations, improved compliance, and an enhanced
suitability for self-medication. Skin provides an ideal site for the delivery
of drug substances for both local and systemic effects. However, it also acts
as a mechanical barrier to the penetration of many drug substances.

In a
survey by Frost & Sullivan, reported in the July/August 2014 issue of Drug
Development & Delivery, physicians indicated that they prefer topical
delivery and are willing to switch to topical delivery from their current mode
of therapy. All of the advantages of topical therapies rely on having the right
formulation. A small change in the formulation can make a large difference in
the efficacy of topical treatments.

With
topical therapies, the formulation is as important as the molecule itself
because the interaction of the vehicle with the skin can alter the efficacy of
the penetrant. The formulation ensures that the drug substance is delivered to
the right target site and that it maintains dosage integrity, drug transport,
and active duration.

For
example, the drug substance in a psoriasis treatment may have some efficacy
simply from the hydrating or soothing effects of the formulation. Whether the
molecule maintains purity, potency, and delivery to the right target site may be
masked by the ingredients that surround it. Both the mechanical barrier
properties of the top layer of skin, stratum corneum, and the physicochemical
properties of the drug affect the transportation of the drug substance from
formulation vehicle to the site of action.

In
addition to the formulation components, a simple change in properties, such as
pH, viscosity, the relative amounts of oil, water, surfactants, stabilizers,
droplet size, ionic nature, or the method of preparation, can often influence skin absorption
and efficacy.

Good
formulation development should have preformulation studies and careful
selection of excipients, including stabilizers and permeation enhancers, early
stability studies, cell line/tissue toxicological studies, IVRT and skin penetration studies,
and finally formulation development and optimization.

THE RIGHT COMBINATION OF DRUG/EXCIPIENTS

The
selection of the right excipients for topical formulationsis extremely important. The drug
substance may be efficacious,but its
interaction with excipients may alter the following:
​

• Its ability to permeate through skin

• Its stability
through shelf life

• Its ability to not
metabolize in skin

• Its ability to stay
dissolved at right concentrations

• Its capability to
achieve desired release rates

For a recently
developed topical formulation, Tergus optimized an emulsion cream to dissolve
the drug up to a certain concentration. The excipients were chosen to optimize
the solubility of the drug substance and to prevent oil and water phase
separation. However, a change in formulation to increase the drug
concentration, so it could accommodate the toxicology study requirement, resulted
in phase separation due to inadequate emulsifiers. The formulation was redone
to optimize the concentration of emulsifiers, as well as the addition of a
viscosity-building excipient. A non-homogenous cream could have resulted in
erroneous toxicology outcomes.

For another project,
Tergus worked with a novel molecule that had undergone preformulation,
solubility, and selection of excipients. Analysis showed drug substance
degradation and increasing impurity levels. Forced degradation studies were
performed to prove which kind of degradation was affecting the molecule.

It was discovered the
drug was undergoing oxidative degradation in the formulation. Steps were taken
to prevent oxidation through the careful selection of excipients, limit
exposure to atmosphere, and minimize drug degradation. Investigation into
the root causes were conducted and found that trace levels ofperoxides were in one
of the excipients. Early stage development used the same excipient in a pure
grade, so oxidation was not prevalent. During scale-up, another supplier of the
same excipient was chosen, and this particular supplier’smaterial had low
levels of peroxides which degraded the drug substance.

Once the cause of
oxidation was determined, the formulation was manufactured with the right grade
of the excipient.

During the early
stages of development of topical formulation, attention must be given to the
permeation enhancers. The bioavailability of the drug in the desired location,
ie, epidermis or dermis, must be considered when choosing the right excipient.
A solvent that forms a depot of drug concentration may not be ideal for a drug
that has site of action in stratum corneum or epidermis.

Similarly, during a
product development project at Tergus, it was discovered during skin permeation
studies that the efficacy was best when two permeation enhancers were combined.
Early detection of such issues is crucial and helps in selection of right formulation
before expensive clinical trials are conducted.

While researching
excipient compatibility and selection for drug substances/peptides targeted to
the dermis, it was discovered that impurities rose in line with
increasing pH of 4-7. In skin permeation studies, the release of the peptide
was very poor. Homogenates of epidermal and dermal layers of skinat different periods
of time showed more stability of the peptide in the dermal layer when compared
to the epidermal layer. By explaining the peptide concentration in skin
tissues, Tergus found that the peptide was going through degradation
with proteolytic enzymes.

Formulation
optimization proved that a more acidic environment delivered the peptide to the right
target layer while avoiding degradation and maintaining efficacy. The pH in
formulations, particularly how it reacts to pH factors in different layers of
skin, is very important. The epidermal layer is more acidic, acting as a
defense and barrier, so creating a more acidic environment forthe formulation
allowed this particular peptide to be delivered to the target site.

IMPACT OF MANUFACTURINGPROCESS PARAMETERS

It is a
well-known fact that scale upand
certain other process parametersimpact
the drug release rate from theformulation.
The FDA has developedguidance
for the industry to study theimpact of
Scale Up and Post ApprovalChanges (SUPAC)
for the marketedproduct.
The same principles can beapplied
to the study of the impact ofmanufacturing
process parameters inchoosing
the right formulation.

The
amount of shear produced bythe
equipment during the emulsificationcan
impact the formulation. In a recentproject,
the formulation for Phase IIsupplies was
being scaled up from PhaseI. The
viscosity differences led to theneed for
process optimization to preventproduct
efficacy differences between twophases of
clinical study.

In
another project, the order ofaddition
of the drug phase made a hugedifference
in drug stability/compatibilitywith the
formulation excipients. The drug-solventsolution
was added to the creamwhen it
was cooled to 40°C, as opposed to adding
it to water phase at 70°C. By making this change in the order ofaddition,
the drug stayed in solution without precipitation. If not addressed early and
if the right formulation manufacturing process was not chosen, expensive
late-stage development efforts would have been needed to addressdrug crystallization
issues.

BARRIERS & CELLULAR DRUGINTERACTIONS

The
epidermal and dermal barriers inhibit drug transport. The right excipient selection
can minimize surface adsorption, have less immunogenicity,and avoid
degradation.

While
performing formulation optimization studies, to also study the viability of
different epidermal and dermal cells allows us to know the dermatological
factor compatibility and to find the proper selection of excipients. The analysis
of drug/peptide levels in different skin tissue barrier homogenates will allow
the researchers to measure the drug/peptide stability and to also find where
the drug is targeting.

Topical
formulation products that are involved in different cellular interactions depend on
the drug action, skin metabolism, pharmaceutical, anddermatological
factors.

FORMULATION FOR UNSTABLEMOLECULES

Tergus
conducted formulation, scale up, and tech transfer work on a molecule that was
unstable, temperature sensitive, and converted to an isomer. Initial drugloading
was 97%, which fell to 50% after 1 month. The challenge was to find a formulation
that increased stability and maintained potency.

Because
the drug substance was very potent, very low concentrations were needed for
therapeutic efficacy. A specific mixture of solvents/viscosity builders
were needed to optimize the formulation and improve scale up.

SUMMARY

The type
of optimal formulation isdetermined
by the properties of the drug substance,
excipients, and the intended target area. Great improvements can befound by considering
both the properties of the skin and the properties of the drug substance/excipients.
Topical formulation selection is also based on the type of cellular transport
and can be analyzed during skin-permeation studies.

The
importance of the right formulation and delivery method in topical pharmaceuticals
is critical. It can mean the success or failure of drug substance. Getting the
preparation right from the outset saves money and time.

Dr.
Vijendra Nalamothu isCEO and Cofounderof
Tergus,which specializes in complete
topical development services, analysis, testing, manufacturing for clinical
trials, and regulatory support. Dr. Nalamothu earned his PhD in Pharmaceutics
from University of the Science’s Philadelphia College of Pharmacy. His efforts
over the past 18 years in various dermatological companies have led to many
commercial products in the market today. Dr. Nalamothu draws from his
exceptional background that combines scientific study with pragmatic, hands-on
experience to solve R&D challenges. He has co/authored numerous publications
and has patents for a few of his inventions. He serves as a member of the
Society for Investigative Dermatologyand the
AAPS and CRS. Dr. Nalamothu also serves on the board of Pharmaceutical and
Technology companies and is a member of several pharmaceutical research focus
and discussion groups.